Stem cell manufacturing system, stem cell information management system, cell transport apparatus, and stem cell frozen storage apparatus

ABSTRACT

A stem cell manufacturing system for manufacturing stem cells from somatic cells includes: one or more closed production device(s) configured to produce stem cells from somatic cells; one or more drive device(s) configured to be connected with the production device(s) and drive the production device(s) in such a manner as to maintain the production device(s) in an environment suitable for producing stem cells; one or more cryopreservation device(s) configured to cryopreserve the produced stem cells; a first memory device configured to store whether or not somatic cells have been introduced to the production device(s), as a first state; a second memory device configured to store whether or not the production device(s) is/are connected with the drive device(s), as a second state; and a third memory device configured to store whether or not the produced stem cells can be placed in the cryopreservation device(s), as a third state.

RELATED APPLICATIONS

The present application is a U.S. Divisional Patent Application whichclaims priority from U.S. application Ser. No. 15/442,755, filed Feb.27, 2017, which is a Continuation-in-part of U.S. application Ser. Nos.15/228,017 and 15/228,022, both filed Aug. 4, 2016, the disclosures ofwhich are hereby incorporated by reference herein in their entireties.

1. Field of the Invention

The present invention relates to a manufacturing technique ofpluripotent stem cells, and in particular to a stem cell manufacturingsystem, a stem cell information management system, a cell transportapparatus, and a stem cell frozen storage apparatus.

2. Description of the Related Art

Embryonic stem cells (ES cells) are stem cells established fromearly-stage embryos of humans or mice, and they are pluripotent, or ableto differentiate into any cells present in a living body. Human ES cellsare considered potentially useful for cell transplantation in thetreatment of many diseases such as Parkinson's disease, juvenilediabetes, and leukemia. ES cell transplant, however, has a drawback ofcausing a rejection, just like organ transplants. Besides, use of EScells is controversial from an ethical point of view because they areestablished by destroying human embryos.

Professor Shinya Yamanaka of Kyoto University succeeded in establishinginduced pluripotent stem cells (iPS cells) by introducing four genes,Oct3/4, Klf4, c-Myc, and Sox2 into somatic cells, and he was awarded a2012 Nobel Prize in Physiology or Medicine (see, for example, JapaneseExamined Patent Publication (Kokoku) No. 4183742). Being idealpluripotent cells that do not cause rejection nor involve ethicalissues, iPS cells are received with high expectations for use in celltransplant.

SUMMARY OF INVENTION

Induced stem cells like iPS cells are established by introducinginducing factors such as genes into cells, and then expanded andcryopreserved. However, there are problems as described below inproducing iPS cells for clinical application (GLP, GMP grades) on anindustrial scale.

1) Expenses

iPS cells for clinical application are produced and cryopreservedpreferably in a clean room that is kept very clean. However, clean roomsare very expensive to maintain. Using clean rooms efficiently to reducecosts is a task to be addressed in achieving industrial use of iPScells.

2) Quality

The processes from establishing stem cells to cryopreserving theminvolve a series of complicated work carried out by hand. Besides,production of stem cells depends much on individual skills. Accordingly,qualities of iPS cells can vary depending on the individuals engaged inthe production of cells. Qualities also vary day by day during the cellproduction. The qualities of iPS cells also depend on the qualities ofthe somatic cells from which they are derived. It is therefore importantto properly manage the time and the temperature for transportation ofsomatic cells until they are received, to properly managecharacteristics of somatic cell donors (sex, age, anamnesis, geneticbackground, and the like), and to properly manage combinations of thesevarious different pieces of information.

3) Time

To avoid cross contamination of somatic cells or iPS cells amongdifferent individuals, iPS cells are produced in a clean room for onlyone individual at one time. In addition, it takes a long time toestablish iPS cells and to evaluate the quality of established cells. Itwould take many years to produce iPS cells for many individuals in wantof iPS cells by producing iPS cells for each of the individuals in oneroom. Thus a system capable of concurrently producing iPS cells for aplurality of individuals in want of iPS cells is desired. Furthermore,since cultured cells are living, they will die unless delivered,processed and frozen at appropriate timings. Especially in a concurrentproduction of iPS cells, unless integrated management is in place tocontrol all the schedules including collecting somatic cells,establishing iPS cells, and cryopreserving them, it is not possible totimely provide iPS cells for many individuals in want of them.

4) Contamination

The first and foremost pollutants in clean rooms are humans, and theirremoval from the rooms is the first priority. In addition, even if iPScells for a plurality of individuals in want are successfully producedon a large scale and concurrently, contamination remains difficult toprevent unless all the processes, including collecting somatic cells,establishing stem cells, and cryopreserving them, are arranged to becompleted in a closed system. Besides, concurrent manufacturing of cellswill increase the risk of erroneous identification of manufacturingsamples and cross contamination.

5) Human Resources

As described above, much of the work for producing iPS cells is carriedout by hand, and only a few experts can produce iPS cells for clinicalapplication. The problem is that the processes from establishing stemcells to cryopreserving them involve a series of complicated work.Culturing cells for clinical application involves three steps, i.e.,checking the standard operation procedure (SOP), operation according tothe SOP, and checking whether the operation has been conducted inaccordance with the SOP. It is very inefficient for humans to executethese steps. Human execution of these steps may lead to erroneousidentification of somatic cells of a plurality of individuals in want ofiPS cells, erroneous identification of culture reagents or materials forproducing iPS cells, or human errors including procedural errors.Furthermore, since cell culture involves management for 24 hours everyday and stem cells are cryopreserved for decades, there is a limit onwhat human efforts can do to achieve adequate management.

Therefore, there is a desire for a technique for producing andcryopreserving stem cells in a timely manner while preventingcontamination, based on an inexpensive but sophisticated qualitymanagement.

According to an aspect of the present disclosure, provided is a stemcell manufacturing system for manufacturing stem cells from somaticcells, the system including: one or more closed production device(s)configured to produce stem cells from somatic cells; one or more drivedevice(s) configured to be connected with the production device(s) anddrive the production device(s) in such a manner as to maintain theproduction device(s) in an environment suitable for producing stemcells; one or more cryopreservation device(s) configured to cryopreservethe produced stem cells; a first memory device configured to storewhether or not somatic cells have been introduced to the productiondevice(s), as a first state; a second memory device configured to storewhether or not the production device(s) is/are connected with the drivedevice(s), as a second state; and a third memory device configured tostore whether or not the produced stem cells can be placed in thecryopreservation device(s), as a third state.

According to another aspect of the present disclosure, provided is astem cell information management system for performing an integratedmanagement of information in an entry process of making an entry of amanufacturing request for manufacturing stem cells from somatic cells, atransport process of transporting somatic cells collected from a somaticcell donor or stem cells produced from the somatic cells, an examinationprocess of examining the somatic cells or the stem cells, amanufacturing process of manufacturing the stem cells from the somaticcells, and a stock process of stocking the stem cells, the systemincluding: a memory unit configured to store a collection schedule forcollecting the somatic cells from the somatic cell donor, an examinationschedule for examining the somatic cells, a production schedule for oneor more production device(s) configured to produce the stem cells fromthe somatic cells, a cryopreservation schedule for one or morecryopreservation device(s) configured to cryopreserve the produced stemcells, and a stock schedule for a stock site at which thecryopreservation device(s) is/are stocked; and a determination unitconfigured to determine at least a collection date for collecting thesomatic cells from the somatic cell donor, based on the storedcollection schedule, the examination schedule the production schedule,the cryopreservation schedule, and the stock schedule.

According to still another aspect of the present disclosure, provided isa cell transport apparatus for transporting somatic cells collected froma somatic cell donor(s) to one or more closed production device(s)configured to produce stem cells from somatic cells, or for transportingthe stem cells to a stem cell stock site, the apparatus including: asomatic cell collection vial for containing the collected somatic cellsand equipped with a first individual identification device containingdonor identification information for identifying the somatic cell donorand production device identification information for identifying theproduction device, or a stem cell freezing vial for containing stemcells produced in the production device and subsequently frozen andequipped with a second individual identification device containing thedonor identification information, the production device identificationinformation, and stock site identification information for identifying astock site for stocking the stem cells; a transport container configuredto contain one or more of the somatic cell collection vials or one ormore of the stem cell freezing vials; a reader device configured to readat least one of the donor identification information, the productiondevice identification information, and the stock site identificationinformation contained in the first individual identification device orthe second individual identification device; and a transport means fortransporting the transport container containing the somatic cellcollection vial or the stem cell freezing vial, based on the readproduction device identification information or stock siteidentification information.

According to still another aspect of the present disclosure, provided isa stem cell frozen storage apparatus for cryopreserving stem cellsproduced from somatic cells collected from a somatic cell donor, theapparatus including: a stem cell freezing vial(s) released from one ormore closed production device(s) and containing frozen stem cells; oneor more cryopreservation device(s) configured to cryopreserve the stemcell freezing vial(s); a storehouse that stores the cryopreservationdevice(s); and a first conveyer device configured to convey thecryopreservation device(s) into and out of the storehouse, thecryopreservation device(s) including: a container unit configured tocontain one or more of the stem cell freezing vials, and a refrigerantchamber configured to contain a refrigerant for freezing the stem cellfreezing vial(s).

According to yet another aspect of the present disclosure, provided is astem cell information management system including: a terminal apparatusthat receives a request for manufacturing stem cells; and a serverapparatus that manages a step of accepting somatic cells for producingthe stem cells, a step of manufacturing stem cells, a step of stockingthe produced stem cells, and a step of transporting the produced stemcells; wherein the terminal apparatus includes: an entry unit that makesan entry of the manufacturing request, including a desired collectiondate of the somatic cells, as well as donor identification informationfor identifying the somatic cell donor; and a terminal sending unit thatsends the entered manufacturing request and the entered donoridentification information to the server apparatus; and wherein theserver apparatus includes: a memory unit that stores a collectable dateon which the somatic cells can be collected, producible period duringwhich the stem cells can be produced, and a stockable location and astockable period where the produced stem cells can be stocked; areceiving unit that receives the sent manufacturing request and the sentdonor identification information; a determination unit that: determinesa collection date of the somatic cells based on the desired collectiondate included in the entered manufacturing request and the storedcollectable date, determines a production period of the stem cells basedon the determined collection date of the somatic cells and the storedproducible period, determines an acceptance date of the somatic cellsbased on the determined collection date of the somatic cells and thestored producible period, determines a stock location and a stock periodfor stocking the produced stem cells, based on the determined productionperiod and the stored stockable location and stockable period, anddetermines a shipping date of the produced stem cells based on thedetermined production period and the stored stockable location andstockable period; a memory processing unit that stores, in the memoryunit, the determined collection date of the somatic cells, thedetermined production period, the determined acceptance date of thesomatic cells, the determined stock location and stock period, and thedetermined shipping date of the stem cells in association with thereceived donor identification information; and a server sending unitthat sends the collection date of the somatic cells, the productionperiod, the acceptance date of somatic cells, the stock location andstock period, and the shipping date of stem cells, stored in associationwith the donor identification information, to the somatic cell donorrepresented by the stored donor identification information.

According to yet still another aspect of the present disclosure,provided is a stem cell information management system including: anentry management terminal that receives a request for manufacturing stemcells; an acceptance management terminal that manages an acceptance ofsomatic cells for producing the stem cells; a manufacturing processmanagement terminal that manages a step of manufacturing the stem cells;and a stock management terminal that manages a stock of the producedstem cells; wherein the entry management terminal includes: a firstmemory unit; an entry unit that makes an entry of the manufacturingrequest including a desired collection date for collecting the somaticcells, as well as donor identification information for identifying thesomatic cell donor; a first determination unit that determines acollection date of the somatic cells based on the desired collectiondate included in the entered manufacturing request; a first output unitthat outputs the determined collection date of the somatic cells to afirst medium; and a first memory processing unit that stores, in thefirst memory unit, the determined collection date of the somatic cellsin association with the entered donor identification information;wherein the acceptance management terminal includes: a second memoryunit that stores a collectable date on which the somatic cells can becollected; a second output unit that outputs the stored collectabledates to a second medium; a second determination unit that determines anacceptance date of the somatic cells based on the collection date of thesomatic cells communicated by the first medium; and a second memoryprocessing unit that stores the determined acceptance date of somaticcells in the second memory unit; wherein the manufacturing processmanagement terminal includes: a third memory unit that stores producibleperiods during which the stem cells can be produced; a thirddetermination unit that determines a production period of the stem cellsbased on the collection date of the somatic cells, communicated by thefirst medium and the stored producible period, and that determines ashipping date of the produced stem cells based on the determinedproduction period of the stem cells; a third output unit that outputsthe stored producible periods of stem cells to a third medium andoutputs the determined production period of the stem cells to a fourthmedium; and a third memory processing unit that stores, in the thirdmemory unit, the determined production period of the stem cells and thedetermined shipping date of the stem cells; wherein the stock managementterminal includes: a fourth memory unit that stores a stockable locationand a stockable period where the produced stem cells can be stocked; afourth output unit that outputs the stored stockable location andstockable period to a fifth medium; and a fourth determination unit thatdetermines a stock location and a stock period for stocking the producedstem cells, based on the production period of the stem cellscommunicated by the fourth medium and the stored stockable location andstockable period; and wherein the first determination unit determinesthe collection date of the somatic cells based on the desired collectiondate and the collectable date communicated by the second medium, whereinthe second determination unit determines the acceptance date of thesomatic cells based on the collection date of the somatic cells and theproduction period communicated by the third medium, and the thirddetermination unit determines the shipping date of the stem cells basedon the production period of the stem cells and the stockable locationand stockable period communicated by the fifth medium.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a schematic configuration of a stem cellmanufacturing system according to an embodiment.

FIG. 2 is a side view of a somatic cell collection vial, a stem cellfreezing vial, a culture reagent vial, and a stem cell productionmaterial vial according to an embodiment.

FIG. 3A is a cross sectional view of a production device according to anembodiment, and FIG. 3B is a cross sectional view of a drive device, andFIG. 3C is a cross sectional view of the production device connectedwith the drive device.

FIG. 4 is an enlarged cross sectional view of the drive device accordingto an embodiment.

FIG. 5 is a perspective view of the cryopreservation device according toan embodiment.

FIG. 6 is a block diagram of the stem cell manufacturing systemaccording to an embodiment.

FIG. 7 is a functional block diagram of an application of the FIELDsystem to the stem cell manufacturing system according to an embodiment.

FIG. 8 is a flow chart illustrating an operation of the stem cellmanufacturing system according to an embodiment, based on a first stateto a third state.

FIG. 9 is a flow chart illustrating an operation of the stem cellmanufacturing system according to an embodiment, based on a fourthstate.

FIG. 10 is a flow chart illustrating an operation of the stem cellmanufacturing system according to an embodiment, based on a fourthstate.

FIG. 11 is a flow chart illustrating an operation of the stem cellmanufacturing system according to an embodiment, based on a sixth state.

FIG. 12 is a flow chart illustrating an operation of the stem cellmanufacturing system according to an embodiment, based on a seventhstate.

FIG. 13 is a flow chart illustrating an operation of the stem cellmanufacturing system according to an embodiment, based on an eighthstate.

FIG. 14 is a schematic diagram illustrating a server-based configurationof a stem cell information management system according to an embodiment.

FIG. 15 is a block diagram illustrating a server-based configuration ofa stem cell information management system according to an embodiment.

FIG. 16 is a block diagram illustrating a medium-based configuration ofa stem cell information management system according to anotherembodiment.

FIG. 17 illustrates a sequence of the server-based operation of the stemcell information management system according to an embodiment.

FIG. 18 illustrates a sequence of the medium-based operation of the stemcell information management system according to another embodiment.

FIG. 19 illustrates a donors master, a collecting institutions master,and an examination institutions master of the stem cell informationmanagement system according to an embodiment.

FIG. 20 illustrates a manufactures master, a production devices master,and a cryopreservation devices master of the stem cell informationmanagement system according to an embodiment.

FIG. 21 illustrates an entry table and an acceptance table of the stemcell information management system according to an embodiment.

FIG. 22 illustrates a production table, a cryopreservation table, astock site master, and a stock table of the stem cell informationmanagement system according to an embodiment.

FIG. 23 is a block diagram of a somatic cell transport containeraccording to an embodiment.

FIG. 24 is a functional block diagram of a heating and cooling device inthe somatic cell transport container according to an embodiment.

FIG. 25 is a functional block diagram of a somatic cell coagulationmonitoring device in the somatic cell transport container according toan embodiment.

FIG. 26 illustrates a transport table of the stem cell informationmanagement system according to an embodiment.

FIG. 27 is a flow chart illustrating a transport operation of the stemcell information management system according to an embodiment.

FIG. 28 is block diagram of a first examination device according to anembodiment.

FIG. 29 is a functional block diagram of the first examination deviceaccording to an embodiment.

FIG. 30 is a flow chart illustrating an examination operation of thestem cell information management system according to an embodiment.

FIG. 31 is a flow chart illustrating a production operation of the stemcell information management system according to an embodiment.

FIG. 32 is a flow chart illustrating a production operation of the stemcell information management system according to an embodiment.

FIG. 33 is a flow chart illustrating a production operation of the stemcell information management system according to an embodiment.

FIG. 34 is a block diagram illustrating a second examination device anda third examination device according to an embodiment.

FIG. 35 is a functional block diagram of the second examination deviceaccording to an embodiment.

FIG. 36 is a functional block diagram of the third examination deviceaccording to an embodiment.

FIG. 37 is a flow chart illustrating an examination operation of thestem cell information management system according to an embodiment.

FIG. 38 is a functional block diagram of an application of the FIELDsystem to the stem cell information management system according to anembodiment.

FIG. 39 is a perspective view of a somatic cell transport container of acell transport apparatus according to an embodiment.

FIG. 40 is a perspective view of a stem cell transport container of thecell transport apparatus according to an embodiment.

FIG. 41 is a block diagram of the stem cell transport containeraccording to an embodiment.

FIG. 42 is a flow chart illustrating an operation of the cell transportapparatus according to an embodiment.

FIG. 43 is a functional block diagram of an application of the FIELDsystem to the cell transport apparatus according to an embodiment.

FIG. 44 illustrates a schematic configuration of a stem cell frozenstorage apparatus according to an embodiment.

FIG. 45 is a block diagram of the stem cell frozen storage apparatusaccording to an embodiment.

FIG. 46 is a functional block diagram of an application of the FIELDsystem to the stem cell frozen storage apparatus according to anembodiment.

DETAILED DESCRIPTION

Embodiments of the present disclosure will be described in detail belowwith reference to the attached drawings. Throughout the drawings,identical or similar parts are denoted by identical or similar numerals.The embodiments described below are not intended to limit in any way thetechnical scope of the invention described in the appended claims or themeaning of words used therein.

1. Stem Cell Manufacturing System

FIG. 1 to FIG. 6 illustrate configurations of a stem cell manufacturingsystem 100 according to the present embodiment. As illustrated in FIG. 1, the stem cell manufacturing system 100 includes one or more closedproduction devices 101 configured to produce stem cells from somaticcells, and the system can produce stem cells for a plurality ofindividuals in want of stem cells. A sealed vial 102 containing somaticcells is inserted to a closed production device 101, and the productiondevice automatically produces stem cells and releases a sealed vial 103containing frozen stem cells. Released vials 103 are transported to oneor more cryopreservation devices 120 in a timely manner andcryopreserved. Although a system in which iPS cells are produced fromblood cells will be described according to the present embodiment, itshould be understood that the invention can be applied to a system inwhich iPS cells are produced from skin-derived cells, a system in whichsomatic stem cells are produced from other somatic cells, a system inwhich stem cells are produced from animal cells, and other systems.

As illustrated in FIG. 1 , the stem cell manufacturing system 100includes a drive device 130 configured to drive a closed productiondevice 101 in such a manner as to maintain the production device in anenvironment suitable for producing stem cells. The stem cellmanufacturing system 100 further includes a conveyer device 140configured to convey at least one of a plurality of kinds of vials 102to 105 preserved in a preservation device 150 to the production device101, a conveyer device 141 configured to convey the production device101 to the drive device 130 or conveys the drive device 130 to theproduction device 101, and a conveyer device 142 configured to convey astem cell freezing vial 103 released from the production device 101 to acryopreservation device 120. These conveyer devices 140 to 142 arerobots autonomously performing work according to a teaching program, butaccording to another embodiment these conveyer devices 140 to 142 may bea belt conveyer system. According to still another embodiment, two orthree of the conveyer devices 140 to 142 are formed in a unitary body.

Referring to FIG. 1 , the stem cell manufacturing system 100 includes acontrol device 160 connected with the drive device 130, the conveyerdevices 140 to 142, and the cryopreservation device 120 by wired orwireless communication and controlling the drive device 130, theconveyer devices 140 to 142, and the cryopreservation device 120. Thecontrol device 160 is also connected with a superordinate computer 170on a cloud by wired or wireless communication and has access to variouspieces of information acquired in all the processes except themanufacturing process, i.e., in the entry process, the transportprocess, the examination process, and the stock process. Thesuperordinate computer 170 includes at least an entry memory device (seeFIG. 15 , numeral 202) configured to store information on the somaticcell donor upon receiving a request for manufacturing stem cells. Thesuperordinate computer 170 transmits various pieces of information suchas an abnormality alarm to a mobile terminal 180 in a remote location.The mobile terminal 180 may be, for example, a smart phone of thesomatic cell donor.

As illustrated in FIG. 2 , the vials include a somatic cell collectionvial 102 containing collected somatic cells, a stem cell freezing vial103 containing frozen stem cells, a culture reagent vial 104 containinga culture reagent, and a stem cell production material vial 105containing a material other than the culture reagent used for producingstem cells. Although only four kinds of vials 102 to 104 are illustratedin FIG. 2 to facilitate understanding, a plurality of kinds of vialsactually exist. These vials 102 to 104 are equipped with an individualidentification device 106 for identifying individuals. The individualidentification device 106 may be a semi-conductor chip using RFID or thelike, one-dimension code such as the barcode, or a two-dimensional codesuch as QR Code (registered trademark) or SP Code.

The individual identification device 106 as illustrated in FIG. 2 atleast includes a donor ID identifying a somatic cell donor. The conveyerdevices 140 to 142, the drive device 130, and the cryopreservationdevice 120 illustrated in FIG. 1 are equipped with a reader device 107(see FIG. 2 ) configured to read the information from the individualidentification device 106 and are capable of reading the donorinformation from the superordinate computer 170, based on the donor IDread from the vial. Donor information includes, for example, informedconsent, nationality, address, sex, age, blood type, anamnesis,prescription history, health check results, and the family members fromwhom stem cells were produced in the past, of the somatic cell donor.According to another embodiment, the individual identification device106 may contain such donor information, and in that case, the donorinformation is encrypted.

In addition to the donor ID, the individual identification device 106illustrated in FIG. 2 includes at least one of an entry ID foridentifying a taking of a request for manufacturing stem cells, atransport ID for identifying a transport of vials, an acceptance ID foridentifying an acceptance of vials, a manufacturer ID for identifying astem cell manufacturer, a production device ID for identifying aproduction device, a cryopreservation device ID for identifying acryopreservation device, and a stock site ID for identifying a stocksite in which the cryopreservation device is to be stocked. This ensurestraceability in case of abnormality in each of the processes fromreceiving a request for manufacturing stem cells to stocking stem cells.Based on the production device ID read from the vial, the conveyerdevice 140 illustrated in FIG. 1 identifies the production device 101 towhich the somatic cell collection vial 102 will be conveyed. Similarly,based on the drive device ID read from the vial, the conveyer device 141conveys the production device 101 to the drive device 130 or conveys thedrive device 130 to the production device 101. Further, based on thecryopreservation device ID read from the vial, the conveyer device 142conveys the stem cell freezing vial 103 to the cryopreservation device120.

As illustrated in FIG. 1 , the conveyer device 140 further includes avision sensor 143 for acquiring data to be used for inputting whether ornot the somatic cell collection vial 102 has been introduced to theproduction device 101 (a first state), and transmits the acquiredinformation indicating the first state to the control device 160. Theconveyer device 141 includes a vision sensor 144 for acquiring data tobe used for inputting whether or not the production device 101 isconnected with the drive device 130 (a second state), and transmits theacquired information indicating the second state to the control device160. The conveyer device 142 includes a vision sensor 145 for acquiringdata to be used for inputting whether or not the stem cell freezing vial103 may be placed in the cryopreservation device 120 (a third state),and transmits the acquired data indicating the third state to thecontrol device 160.

According to another embodiment, as illustrated in FIG. 3B and FIG. 4 ,the drive device 130 may include switches 153 to 155 for outputtingelectrical signals for inputting at least one of the first to the thirdstates, and transmit a signal indicating at least one of the first tothe third states to the control device 160. According to still anotherembodiment, as illustrated in FIG. 5 , the cryopreservation device 120may include a presence sensor 121 for detecting a presence of a stemcell freezing vial 103 for inputting the third state, and transmitinformation indicating the third state to the control device 160.According to yet another embodiment, an input device (not illustrated)configured to manually input at least one of the first to the thirdstates may be included. The input device may be a liquid crystal touchpanel, a keyboard, or a mouse provided for the control device 160, amanufacturing process management terminal (see FIG. 15 and FIG. 16 ), orthe like.

As illustrated in FIG. 6 , the conveyer devices 140 to 142 (which arerepresented solely by the conveyer device 140 in FIG. 6 ) each include aCPU 147 that causes a memory 146 to store information indicating atleast one of the above-described first to the third states. In anotherembodiment, the drive device 130 may include the CPU 132 that causes amemory 131 to store information indicating at least one of theabove-described first to the third states. According to yet anotherembodiment, the cryopreservation device 120 may include a CPU 123 tocause a memory 122 to store information indicating the above-describedthird state.

FIG. 8 is a flow chart illustrating an operation based on the firststate to the third state in the stem cell manufacturing system 100according to the present embodiment. When the conveyer device 140 hasdetermined by using the vision sensor 143 that the somatic cellcollection vial 102 has not been introduced in the production device 101(step S100), the conveyer device 140 stores information indicating thefirst state in the memory 146, in association with the donor ID readfrom the vial (step S101). When the conveyer device 141 has determinedby using the vision sensor 144 that the production device 101 is notconnected with the drive device 130 (step S102), the conveyer device 141stores information indicating the second state in the memory 147, inassociation with the donor ID read from the vial (step S103). Theconveyer device 140 then conveys at least one of the somatic cellcollection vial 102, the stem cell freezing vial 103, the culturereagent vial 104, and the stem cell production material vial 105 to theproduction device 101 (step S104), and the conveyer device 141 connectsthe production device 101 with the drive device 130 (step S105).Subsequently, when the conveyer device 142 has determined by using thevision sensor 145 that stem cell freezing vial 103 has been releasedfrom the production device 101 and that the stem cell freezing vial 103may be placed in the cryopreservation device 120 (step S106), theconveyer device 142 stores information indicating the third state in amemory 148, in association with the donor ID read from the vial (stepS107). The conveyer device 142 then conveys the stem cell freezing vial103 to the cryopreservation device 120 (step S108).

As illustrated in FIG. 3A, the production device 101 includes anisolation device 108 that receives the somatic cell collection vial 102and isolates cells from the blood, and the drive device 130 includes apump 133 that transfers suspension containing isolated mononuclear cellsin a pre-introduction cell transfer fluid path 109. The productiondevice 101 further includes a factor introducing device 110 including anelectroporator, that introduces pluripotency-inducing factors into theisolated mononuclear cells to produce inducing-factor-introduced cells,and the drive device 130 includes a pump 134 for transferring solutioncontaining inducing-factor-introduced cells through a factor-introducedcell transfer fluid path 111. The production device 101 also includes aninitial culture device 112 for culturing the inducing-factor-introducedcells, and the drive device 130 includes a pump 135 for transferringfluid containing the cultured stem cell clusters and atrypsin-substituting recombinant enzyme in a first cell cluster transferfluid path 113. The production device 101 further includes an expansionculture device 114 that receives a solution containing stem cellclusters separated by sieving in a mesh or the like in the first cellcluster transfer fluid path 113 and places the solution in wells torepeat expansion culture, and the drive device 130 includes a pump 136for transferring fluid containing expansively cultured stem cellclusters through the second cell cluster transfer fluid path 115. Theproduction device 101 further includes a cell cluster transfer mechanism117 that receives a solution containing stem cell clusters separated bysieving in a mesh or the like in the second cell cluster transfer fluidpath 115 and transfers in order the separated cell clusters to apre-package cell fluid path 116, and a packaging device 118 that placesin order portions of solution containing stem cell clusters, transferredthrough the pre-package cell fluid path, into a stem cell freezing vial103, and freezes the solution instantaneously by using liquid nitrogenor the like.

As illustrated in FIG. 4 , the drive device 130 further includes avision sensor 137 configured to acquire data in the production device101 and, based on the data from the vision sensor 137, stores whether ornot the stem cells are being produced in a normal condition as a fourthstate in numerical form in the memory 131. Such a fourth state mayinclude the size or growth speed of stem cell clusters in the initialculture device 112 and the expansion culture device 114, the ratiobetween stem cell clusters of different sizes, color tone or pH ofculture reagent, and the like.

The drive device 130 further includes a temperature sensor 138configured to detect temperature in the production device 101 and, basedon the temperature from the temperature sensor 138, stores whether stemcells are being produced in a normal condition as a fourth state innumerical form in the memory 131. Such a fourth state may include aresistance, voltage, and the like of the temperature sensor in theinitial culture device 112 or the expansion culture device 114.

According to another embodiment, the drive device 130 may include anexamination window (not illustrated) for conducting an visualexamination into the production device 101 and, based on the visualexamination through the examination window done by the operator, whetheror not stem cells are being produced in a normal condition may manuallyinputted to be stored in the memory 131 as a fourth state in numericalform. Such a fourth state may include the size or growth speed of stemcell clusters in the initial culture device 112 and the expansionculture device 114, the ratio between stem cell clusters of differentsizes, color tone of culture reagent.

According to the present embodiment, the drive device 130 furtherincludes a removal outlet 139 for taking out a sample released from theproduction device 101 and, based on the sample taken out, stores whetherthe stem cells are being produced in a normal condition as a fourthstate in numerical form in a memory. Such a fourth state may be, forexample, the number of stem cells, the size of stem cells, the ratiobetween stem cell clusters of different sizes, the shape of stem cells,the presence or absence of differentiated cells having differentiatedfrom the stem cells, or the like, which is measured by using a flowcytometer, a cell sorter, or the like.

According to another embodiment, the drive device 130 further includes adisplay device (not illustrated) configured to display data in theproduction device 101 and, based on a visual examination of displayeddata, whether or not the stem cells are in a normal condition may bemanually inputted to be stored in the memory 131 as a fourth state innumerical form. Such a fourth state may be, for example, the size orgrowth speed of stem cell clusters, the ratio between stem cell clustersof different sizes, the stem cell count, the shape of stem cells, thecolor tone of culture reagent, or the like. According to still anotherembodiment, such a display device is not the drive device 130 but may bea liquid crystal monitor provided for the control device 160, amanufacturing process management terminal (see FIG. 15 and FIG. 16 ), orthe like. The drive device 130 also stores at least one of the normalrange and the abnormal range of the fourth state in the memory 131 asfirst information.

FIG. 9 is a flow chart illustrating an operation of the stem cellmanufacturing system 100 according to the present embodiment, based onthe fourth state. When the drive device 130 has determined that the stemcells are not being produced in a normal condition (i.e., informationindicating the fourth state (e.g., the ratio of stem cell clustershaving a size not less than 100 μm after the initial culture, or theratio of stem cell clusters having a size of not more than 30 μm in 14days) is out of the stored normal range or within the abnormal range(not less than 80%)) (step S110), the drive device 130 stores theinformation indicating the fourth state in the memory 131, inassociation with the donor ID read from the vial (step S111). The drivedevice 130 then outputs a first abnormality alarm in association withthe donor ID and transmits the abnormality alarm to the mobile terminal180 in a remote location via the control device 160 and thesuperordinate computer 170 (step S112). The drive device 130 then comesto a halt, and the production of stem cells is suspended (step S113).The drive device 130 then cleans the inside of the production device 101with cleaning liquid (step S114) and changes the culture reagent (stepS115). The drive device 130 requests the superordinate computer 170 viathe control device 160 to rearrange the production schedule for theproduction device 101 (step S116). According to another embodiment,after the drive device 130 comes to a halt in step 113, the conveyerdevice 141 may connect a different production device 101 to the drivedevice 130 to produce stem cells again.

FIG. 10 is a flow chart illustrating an operation of the stem cellmanufacturing system 100 according to the present embodiment, based onthe fourth state. As illustrated in FIG. 10 , when the drive device 130has determined that the stem cells are not being produced in a normalcondition (i.e., information indicating the fourth state (e.g., thegrowth speed of the stem cell clusters in the expansion culture) is outof the stored normal range or within the abnormal range (not more than 2μm/h)) (step S120), the drive device 130 stores the informationindicating the fourth state in the memory 131, in association with thedonor ID read from the vial (step S121). The drive device 130 thenoutputs a first abnormality alarm in association with the donor ID andtransmits the abnormality alarm to the mobile terminal 180 in a remotelocation via the control device 160 and the superordinate computer 170(step S122). The drive device 130 then adjusts the amount of the culturereagent (for example, by increasing the amount of fibroblast growthfactor by 5%) (step S123), adjusts the carbon dioxide concentration inthe initial culture device 112 and the expansion culture device 114 (forexample, by increasing CO₂ concentration from 5% to 10%) (step S124),and extends culturing time (for example, by one week) (step S125). Thedrive device 130 then requests the superordinate computer 170 via thecontrol device 160 to rearrange the production schedule for theproduction device 101 (step S126).

Referring once again to FIG. 1 , the conveyer device 140, by using thevision sensor 143, stores respective inventory quantities of the vials102 to 105 preserved in the preservation device 150 and respectivearrival schedules of the vials 102 to 105 as a fifth state in the memory146, and transmits information indicating the fifth state to the controldevice 160. The control device 160 stores the received informationindicating the fifth state in a memory 161. According to anotherembodiment, the preservation device 150, by using the vision sensor 151,may store respective inventory quantities of the vials 102 to 105preserved in the preservation device 150 and respective arrivalschedules of the vials 102 to 105 as a fifth state in the memory 152,and transmit the information indicating the fifth state to the controldevice 160 by wired or wireless communication.

FIG. 11 is a flow chart illustrating an operation of the stem cellmanufacturing system 100 according to the present embodiment, based onthe sixth state. The control device 160 compares information indicatingat least one of the first to the fifth states, received from theconveyer devices 140 to 142, the drive device 130, and thecryopreservation device 120, with a predefined standard state (e.g., thestandard operation procedure (SOP)) (step S130), and stores the presenceor absence of a difference (the sixth state), in the memory 161 inassociation with the donor ID (step S131). When there is a differencebetween the predefined standard state and information indicating atleast one of the first to the fifth states (step S132), the controldevice 160 outputs a second abnormality alarm in association with thedonor ID and transmits the second abnormality alarm to the mobileterminal 180 in a remote location via the superordinate computer 170(step S133). The control device 160 causes the drive device 130 to cometo a halt (step S134). According to another embodiment, the conveyerdevices 140 to 141 may compare the information indicating the firststate and the second state with the predefined standard state (SOP), thecryopreservation device 120 may compare the information indicating thethird state with the predefined standard state (SOP), and the drivedevice 130 may compare the information indicating the fourth state withthe predefined standard state (SOP). According to still anotherembodiment, in the above-described step S130 to step S131, the controldevice 160 may compare not the first to the fifth states but other workitems with the SOP to determine whether or not the other work items arecarried out properly, and store the presence or absence of a differencein association with the donor ID in the memory 161.

FIG. 5 is a perspective view of the cryopreservation device according tothe present embodiment. The cryopreservation device 120 includes acontainer unit 124 containing one or more stem cell freezing vials 103,a vacuum insulated refrigerant chamber 125 configured to contain arefrigerant for cryopreserving the stem cell freezing vial(s) 103 (e.g.,liquid nitrogen in the liquid phase at −180° C. or lower and the gasphase at −160° C. or lower), and a supply valve 126 for supplying therefrigerant in advance.

The cryopreservation device 120 further includes a vision sensor 127 foracquiring data in the cryopreservation device 120 and, based on the datafrom the vision sensor 127, stores in the memory 122 whether or not thestem cells are being stored in a normal condition (see FIG. 6 ) as aseventh state in numerical form. Such a seventh state may be, forexample, the presence or absence of stem cells (or the presence orabsence of frozen liquid) in the stem cell freezing vials 103.

The cryopreservation device 120 also includes a temperature sensor 128configured to detect temperature in the cryopreservation device 120 and,based on the temperature from the temperature sensor 128, stores in thememory 122 whether or not the stem cells are being stored in a normalcondition as a seventh state in a numerical from. Such a seventh statein numerical form may be, for example, resistance and voltage of thetemperature sensor, or temperature obtained from these. Stem cells arepreferably stored at temperatures at −160° C. or lower, and may sustaina serious damage or may perish when they undergo a temperature change ofabout 20° C.

The cryopreservation device 120 further includes a refrigerant remainingamount sensor 129 configured to detect the remaining amount ofrefrigerant in the cryopreservation device 120 and, based on theremaining amount from the refrigerant remaining amount sensor 129,stores in the memory whether or not the stem cells are being stored in anormal condition as a seventh state in a numerical from. Such a seventhstate may be, for example, voltage or resistance of the remaining amountsensor. The cryopreservation device 120 stores at least one of thenormal range and the abnormal range of the seventh state as secondinformation in the memory 122.

FIG. 12 is a flow chart illustrating an operation of the stem cellmanufacturing system 100 according to the present embodiment, based onthe seventh state. When the cryopreservation device 120 has determinedthat the stem cells are not being stored in a normal condition (i.e.,when the information indicating the seventh state (e.g., the temperaturefrom the temperature sensor) is out of the normal range or within theabnormal range (over −160° C.) stored in memory) (step S140), thecryopreservation device 120 stores the information indicating theseventh state in the memory 122 in association with the donor ID readfrom the vial (step S141). The cryopreservation device 120 then outputsa third abnormality alarm in association with the donor ID and transmitsthe third abnormality alarm to the mobile terminal 180 in a remotelocation via the control device 160 and the superordinate computer 170(step S142).

FIG. 13 is a flow chart illustrating an operation of the stem cellmanufacturing system 100 according to the present embodiment, based onthe eighth state. The control device 160 stores the operation record ofat least one of the conveyer devices 140 to 142, the drive device 130,and the cryopreservation device 120 (the eighth state) in the memory 161in association with the donor ID (step S150). The control device 160then compares the eighth state with a predefined standard state (e.g., astandard operation procedure (SOP)) (step S151), and stores in thememory 161 the presence or absence of a difference (the sixth state) inassociation with the donor ID (step S152). When there is a differencebetween the eighth state and the predefined standard state (step S153),the control device 160 outputs a second abnormality alarm in associationwith the donor ID and transmits the second abnormality alarm to themobile terminal 180 in a remote location via the superordinate computer170 (step S154). According to another embodiment, the conveyer devices140 to 142, the drive device 130, and the cryopreservation device 120store in memory respective operation records (the eighth state) inassociation with the donor ID and compares the eighth state with thepredefined standard state (SOP), and the control device 160 stores thepresence or absence of a difference (the sixth state) in associationwith the donor ID in the memory 161.

The memory that stores at least one of the above-described first to theeighth states may be a single memory provided in a single housing, i.e.,the control device or the superordinate computer 170. At least one ofthe first to the eighth states is transmitted by wireless communicationto the mobile terminal 180 in a remote location.

FIG. 7 is a functional block diagram of an application of the FIELDsystem to the stem cell manufacturing system 100 according to thepresent embodiment. The stem cell manufacturing system 100 furtherincludes a control device 160 including interface software 163 and worksoftware 164, and input devices in wired or wireless communication withthe control device 160 and configured to input information in themanufacturing process. The input devices may be, for example, theabove-described drive device 130, the cryopreservation device 120, andconveyer devices 140 to 142. According to another embodiment, the inputdevices may be, for example, input devices configured to manually inputinformation indicating at least one of the first to the eighth states.

The control device 160, for example, receives inputs of electric currentvalues of the first to the fourth pumps, voltage values of the first tothe third switches, data from the vision sensor, and the like frommoment to moment from one or more drive devices 130, receives inputs ofresistance values of the temperature sensor, temperature data of thetemperature estimation unit, impedance of a somatic cell coagulationmonitoring device, voltage values of the refrigerant remaining amountsensor, data from the vision sensor and the like from moment to momentfrom one or more cryopreservation devices 120, and receives inputs ofelectric current values of servo motors for respective axes, data from avision sensor, and the like from moment to moment from the conveyerdevice 140. Since a large number of input devices of many kinds send outpieces of information unique to a large number of components of manykinds, the control device 160 cannot recognize, for example, by whichpump of which drive device working with which production device acertain flow rate is produced. To address this, the interface software163 converts the information formatted in data formats unique to theinput devices into information formatted in a data format unique to thework software 164. The data format unique to the work software 164 isformed with data models having a data structure of tree type or networktype indicating subordination relationship of the components of eachinput device, and the various data models are stored in the memory 161of the control device 160 in advance. To facilitate understanding, forexample, an electric current value of the first pump of the drive device130, a piece of information unique to the input device, is converted to“drive device ID/production device ID/first pump/electric currentvalue/flow rate”, which is in a structured data format unique to thework software. This conversion gives the work software 164 an instantaccess to data unique to a large number of components of many kinds in alarge number of input devices of many kinds.

According to the above-described stem cell manufacturing system 100, aplurality of closed production devices 101 enable the production of stemcells for a plurality of individuals in want of stem cells on a largescale and concurrently, and the closed FA system, which does not needclean rooms, achieves cost reduction, sophisticated quality control,contamination prevention, and solution of human resource shortage.Furthermore, by applying the FIELD system, the time for producing stemcells is reduced. In addition, by reading various identificationinformation attached to each vial, the stem cell manufacturing system100 prevents cross contamination with somatic cells or stem cells ofother individuals. The stem cell manufacturing system 100 makes a greatcontribution especially for developing an industry in the area of iPScells for clinical use.

2. Stem Cell Information Management System

FIG. 14 is a schematic diagram illustrating a server-based configurationof a stem cell information management system 200 according to thepresent embodiment. The stem cell information management system 200includes a server apparatus 201 on a cloud, and is constituted by acloud system that performs an integral control of big data in an entryprocess of receiving a request for manufacturing stem cells from somaticcells, a transport process of transporting somatic cells collected froma somatic cell donor or stem cells produced from somatic cells, anexamination process of examining somatic cells or stem cells, amanufacturing process of manufacturing stem cells from somatic cells,and a stock process of stocking stem cells. Such a server apparatus 201corresponds to the superordinate computer 170 in other drawings.Although a system in which iPS cells are produced from blood cells willbe described according to the present embodiment, it should beunderstood that the invention can be applied to a system in which iPScells are produced from skin-derived cells, a system in which ES cellsare produced from embryonic cells, and other systems. An outline of theprocessing performed by the stem cell information management system 200will be described first.

In the entry process, upon receiving a request for manufacturing stemcells, the server apparatus 201 determines all the schedules from thestem cells entry process to the stock process such that stem cells willbe produced in a shortest route possible and in a shortest timepossible. Upon receiving the request, the server apparatus 201 stores inthe memory unit 202 donor information including at least one of informedconsent, nationality, address, sex, age, blood type, anamnesis,prescription history, health check results, and family members from whomstem cells are produced in the past, of the somatic cell donor, inassociation with a donor ID. A collection kit 209 including one or moresomatic cell collection vials 102 with the donor ID is then sentspecifically to the somatic cell donor himself or herself, whichprevents handling of the donor's cells in mistake for somatic cells orstem cells of another individual and failure to attach the correct donorID to his or her collected cells. According to another embodiment, sucha collection kit 209 may be sent not only to the somatic cell donorhimself or herself but to the institution at which his or her somaticcells are collected, in advance. The somatic cell collection vial 102includes an individual identification device 106 that contains, inaddition to a donor ID, at least one of an entry ID, a transport ID, anacceptance ID, a manufacturer ID, a production device ID, acryopreservation device ID, and a stock site ID, as illustrated in FIG.2 .

In the transport process of somatic cells, one or more somatic cellcollection vials 102 are placed in a transport container 250, and thetransport container 250 is transported from a collection institution toan examination institution and from the examination institution to astem cell manufacture by transportation means including at least one ofautomobile, railway, aircraft, ship, and robot. At the time oftransport, information on the temperature in the transport container250, accumulated transportation time, vibration and coagulation state ofthe somatic cells and the like is transmitted to the server apparatus201, and the server apparatus 201 performs tasks such as issuing anabnormality alarm and modifying the schedules.

In the examination process of somatic cells, a viral or bacteriologicaltest, a test for blood cell counting, a test for gene expression levelmeasurement, and other tests are conducted on the collected somaticcells. At the time of examination, results of these tests are sent tothe server apparatus 201, and the server apparatus 201 performs taskssuch as issuing an abnormality alarm and modifying the schedules. Inparticular, the server apparatus 201 is characterized by that the serverapparatus 201 determines a predicted reprogramming rate, which serves asan indicator as to whether or not the somatic cells can be reprogrammed,based on correlation data accumulated from past donors between age,anamnesis, presence or absence of family members from whom stem cellswere produced in the past, blood cell count, and presence or absence andmeasurement of expression of particular genes on one hand and thereprogramming data of the somatic cells on the other, and performs taskssuch as issuing an abnormality alarm and modifying the schedules.

In the manufacturing process, information indicating the above-describedfirst state to the eighth states in the stem cell manufacturing system200 is sent to the server apparatus 201, and the server apparatus 201performs tasks such as issuing an abnormality alarm and modifying theschedules. When the production device 101 fails to release a stem cellfreezing vial 103 in accordance with the predicted release date and timeinitially set by the server apparatus 201 at the time of receiving therequest, the server apparatus 201 performs tasks such as outputting anabnormality alarm and modifying the schedules.

In the transport process of stem cells, stem cell freezing vials 103containing stem cells manufactured by the stem cell manufacturer areplaced in the transport container 250 and transported by transportationmeans including at least one of automobile, railway, aircraft, ship, androbot. The transport container 250 includes a cryopreservation device120 containing the above-described refrigerant, but the refrigerant inthe cryopreservation device 120 is released through a safety valve astime elapses and the cryopreservation device 120 accordingly has ashort-time cryopreservation function only. At the time of transport,information regarding not only temperature in the cryopreservationdevice 120, accumulated transportation time, vibration, but alsoremaining amount of refrigerant or remaining amount of reservedrefrigerant is sent to the server apparatus 201, and the serverapparatus 201 performs tasks such as issuing an abnormality alarm andmodifying the schedules.

In the stock process, one or more cryopreservation devices 120 arestocked in the storehouse of a stem cell stock site and refrigerant isstably supplied to the one or more cryopreservation devices 120. Thestem cell stock site accordingly has a long-term cryopreservationfunction. During stock, temperature in the cryopreservation device 120,remaining amount of refrigerant as well as presence or absence of stemcells (or presence or absence of frozen liquid) and the like are sent tothe server apparatus 201, and the server apparatus 201 performs taskssuch as issuing an abnormality alarm and modifying the schedules.

In the examination process of stem cells, genomic information tests ofsomatic cells and stem cells, HLA typing tests of somatic cells and stemcells, and other tests are conducted. At the time of examination,information on test results is transmitted to the server apparatus 201,which performs tasks such as issuing an abnormality alarm and modifyingthe schedules. In particular, the server apparatus 201 is characterizedin that the server apparatus 201 determines whether or not the somaticcells and the stem cells are from the same individual, based on thegenomic information and the HLA types of the somatic cells and the stemcells, and performs tasks such as issuing an abnormality alarm andmodifying the schedules.

FIG. 15 is a block diagram illustrating a server-based configuration ofthe stem cell information management system 200 according to the presentembodiment. The server apparatus 201 includes memory unit 202 storing acollection schedule for collecting somatic cells from a somatic celldonor, an examination schedule for examining the somatic cells, aproduction schedule for one or more closed production devices configuredto produce stem cells from the somatic cells, a cryopreservationschedule for one or more cryopreservation devices configured tocryopreserve the produced stem cells, a stock schedule for the stocksite at which cryopreservation device is stocked, and a determinationunit 203 that, upon receiving a request for manufacturing stem cells,determines a schedule such that stem cells will be produced in ashortest route possible and in a shortest time possible, based on thestored collection schedule, examination schedule, production schedule,cryopreservation schedule, and stock schedule. According to anotherembodiment, the determination unit 203 may determine the schedule basedon a supply schedule of the culture reagent and stem cell productionmaterial.

As illustrated in FIG. 15 , the stem cell information management system200 further includes an entry management terminal 210 connected with theserver apparatus 201 by wired or wireless communication and receiving arequest for manufacturing stem cells, an acceptance management terminal220 that manages acceptance of somatic cells, a manufacturing processmanagement terminal 230 for managing manufacturing process, and a stockmanagement terminal 240 for managing the stocking of stem cells. Theacceptance management terminal 220 stores collectable dates ofcollecting institutions and examinable dates of examination institutionsin the memory unit 211 in advance, and the stock management terminal 240stores stockable locations and stockable periods of stem cell stocksites in the memory unit 241 in advance. According to the presentembodiment, these terminal apparatuses 210 to 240 are disposed in a stemcell manufacturer illustrated in FIG. 14 , but according to anotherembodiment they may be disposed in other locations or be formed in asingle housing.

FIG. 17 illustrates a sequence of an operation of the stem cellinformation management system 200 according to the present embodiment.The server apparatus 201 receives collectable dates on which somaticcells can be collected and examinable dates on which somatic cells canbe inspected from the acceptance management terminal 220 in advance andstores these dates in the memory unit 202 (step S200). According toanother embodiment, the server apparatus 201 may directly receivecollectable dates from the collecting institutions and examinable datesfrom the examination institutions. The server apparatus 201 furtherreceives producible periods of one or more closed production devices 101from the manufacturing process management terminal 230 in advance andstores the periods in the memory unit 202 (step S201). Further, theserver apparatus 201 receives stockable locations and stockable periodsfrom the stock management terminal 240 in advance and stores thestockable locations and stockable periods in the memory unit 202 (stepS202). According to another embodiment, the server apparatus 201 maydirectly receive stockable locations and stockable periods from thestock sites.

When the server apparatus 201 receives a manufacturing request includingdesired collection dates, together with the donor ID from the entrymanagement terminal 210 (step S203), the server apparatus 201 determinesa collection date of somatic cells, based on whether or not the one ofthe desired collection dates falls upon one of the collectable dates(step S204). The server apparatus 201 further determines a transportdate such that a collection kit 209 will be transported seven days priorto the determined collection date (step S205). Further, the serverapparatus 201 determines an examination date of somatic cells, based onwhether or not the date obtained by adding two days for transporting thesomatic cells to the determined collection date falls upon one of theexaminable dates (step S206). The server apparatus 201 furtherdetermines an acceptance date of somatic cells at a stem cellmanufacturer, based on whether or not the date obtained by adding sevendays for examining the somatic cells and two days for transporting thesomatic cells to the determined date of somatic cell examination fallswithin an producible period of one or more closed production devices 101(step S207). Further, the server apparatus 201 determines a stem cellproduction period such that the manufacturing of stem cells may bestarted immediately from the determined acceptance date of somatic cells(step S208). In other words, the server apparatus 201 determines a stemcell production period based on the determined collection date ofsomatic cells and the stored producible periods of one or more closedproduction devices 101. At the time of receiving a request, the serverapparatus 201 initially sets a predicted release date and time of thestem cell freezing vials 103 to be released from the closed productiondevices 101 on a date three months after the date of starting theproduction. The server apparatus 201 then determines a cryopreservationperiod, based on whether or not the predicted release date and time ofthe stem cell freezing vials 103 falls within an cryopreservable periodof one or more cryopreservation devices 120 (step S208). The serverapparatus 201 then determines a stock location and a stock period ofstem cells, based on whether or not the date obtained by adding fourdays for transporting the stem cells to the predicted release date andtime of the stem cell freezing vials 103 falls within a stockable periodof the most closely located stockable location among the stockable sitesstored in memory (step S209). The server apparatus 201 determines a stemcell shipping date, based on the determined production period and thestockable locations and stockable periods stored in memory (step S210).The server apparatus 201 stores in the memory unit 202 the determinedcollection date of somatic cells, the transport date of transporting acollection kit 209, the examination date of somatic cells, theacceptance date of somatic cells, the production period of stem cells,the cryopreservation period of stem cells, the stock location and stockperiod of stem cells, and the shipping date of stem cells in associationwith the donor ID (step S211) and transmits these dates, locations andperiods to the somatic cell donor represented by the donor ID (stepS212). According to another embodiment, the server apparatus 201 maydetermine a cryopreservation period during which somatic cells aretemporarily cryopreserved after it has decided the acceptance date ofsomatic cells in step S207. The cryopreservation period may include, forexample, a period for preserving peripheral blood mononuclear cellsisolated from the blood.

Referring to FIG. 19 to FIG. 22 , how to determine the schedules in theabove-described steps S204 to S211 will be described in detail. FIG. 19to FIG. 22 illustrate a relational database including a donors master500, a collecting institutions master 501, an examination institutionsmaster 502, a manufactures master 503, a production devices master 504,a cryopreservation devices master 505, an entry table 506, an acceptancetable 507, production table 58, a cryopreservation table 509, a stocksite master 510, and a stock table 511, stored in the memory unit of theserver apparatus 201. In the following, a case of the entry ID 0001 ofthe entry table 506 in FIG. 21 will be described. In step S204, thedonors master 500 in FIG. 19 provides an address corresponding to thedonor ID 0102, the collecting institutions master 501 in FIG. 19 revealsthat the collecting institution at the collection site most closelylocated to this address is the one with a collecting institution ID0001, and the second desired collection date 2018 Mar. 16 in the entrytable 506 in FIG. 21 falls upon the first collectable date 2018 Mar. 16in the collecting institutions master 501 in FIG. 19 ; therefore, theserver apparatus 201 determines that the collection date of somaticcells is to be 2018 Mar. 16.

In step S205, by selecting a date seven days prior to the collectiondate of somatic cells 2018 Mar. 16 specified in the entry table 506 inFIG. 21 , the server apparatus 201 determines that the transport date ofthe collection kit 209 is to be 2018 Mar. 9. In step S206, by adding tothe collection date of somatic cells 2018 Mar. 16 two days fortransporting the somatic cells, the date 2018 Mar. 18 is obtained, whichfalls upon the second examinable dates 2018 Mar. 18 of the most closelylocated examination institution in the examination institutions master502 in FIG. 19 ; therefore, the server apparatus 201 determines that theexamination date of somatic cells is to be 2018 Mar. 18. In step S207,referring to the entry table 506 in FIG. 21 , by adding seven days forexamining the somatic cells and two days for transporting the somaticcells to the examination date of somatic cells 2018 Mar. 18, the date2018 Mar. 27 is obtained, and this date falls within the producibleperiod from 2018 Mar. 16 to 2018 Sep. 16 corresponding to themanufacturer ID 0001 specified in the production table 508 in FIG. 22 ;therefore, the server apparatus 201 determines that the acceptance dateof somatic cells is to be 2018 Mar. 27, as illustrated in the acceptancetable 507 in FIG. 21 .

In the case of the entry ID 0003 in the entry table 506 in FIG. 21 ,however, by adding seven days for examining the somatic cells and twodays for transporting the somatic cells to the examination date ofsomatic cells 2018 Mar. 27, the date 2018 Apr. 5 is obtained, which doesnot fall within the producible period corresponding to the manufacturerID 0003 specified in the production table 508 in FIG. 20 ; therefore,the server apparatus 201 issues an alarm for rearranging the schedules,as illustrated in the production table 508 in FIG. 22 , and prompts aninquiry of the somatic cell donor for other desired collection dates.

Returning to the case of the entry ID 0001, in step S208, the serverapparatus 201 determines that the production period is to be from 2018Mar. 27 to 2018 Sep. 16 as illustrated in the production table 508 inFIG. 22 so that the production of the stem cells may be startedimmediately from the acceptance date of somatic cells 2018 Mar. 27. Instep S209, the server apparatus 201 sets the predicted release date andtime of the stem cell freezing vial in FIG. 22 on 2018 Jun. 27, which isthree months after the production starting date 2018 Mar. 27. Since thepredicted release date and time 2018 Jun. 27 falls within ancryopreservable period from 2018 Jun. 18 to 2018 Jul. 17 in thecryopreservation devices master 505 in FIG. 20 , the server apparatus201 determines that the cryopreservation period is to be from 2018 Jun.27 to 2018 Jul. 17, as illustrated in the cryopreservation table 509 inFIG. 22 .

In the case of the entry ID 0002 in the production table 508 in FIG. 22, however, the predicted release date and time 2018 Jul. 2 does not fallwithin any of cryopreservable periods for the manufacturer ID 0002 inthe cryopreservation devices master 505 in FIG. 20 , the serverapparatus 201 issues an alarm for rearranging the schedules, asillustrated in the cryopreservation table 509 in FIG. 22 , and promptsan inquiry of the somatic cell donor for other desired collection dates.

Returning to the case of the entry ID 0001, in step S210, by adding tothe predicted release date and time 2018 Jun. 27 in the production tablein FIG. 22 four days for transport, the date 2018 Jul. 1 is obtained,which date falls within an stockable period 2018 Jun. 16 of the LA stocksite at the most closely located stock location of the stockablelocations in the stock site master 510 in FIG. 22 ; therefore, theserver apparatus 201 determines that the stock location is to be the LAstock site and that the stock period is to be 50 years starting from2018 Jul. 1. In step S211, the server apparatus 201 determines that theshipping date of stem cells is to be 2018 Jun. 27, which is thepredicted release date and time.

FIG. 16 is a block diagram illustrating a medium-based configuration ofa stem cell information management system 260 according to anotherembodiment. The stem cell information management system 260 differs fromthe server-based configuration of the stem cell information managementsystem 260 only insofar as it does not use the server apparatus 201, andotherwise the configuration is the same as the server-basedconfiguration. The stem cell information management system 260 transfersvarious information among terminal apparatuses 210 to 240 by papermedium or telecommunication medium. Since the stem cell informationmanagement system 260 does not use the server apparatus 201 on a cloud,it is secure and prevents personal information from being leaked. Thestem cell information management system 260 includes an entry managementterminal 210, an acceptance management terminal 220, a manufacturingprocess management terminal 230, and a stock management terminal 240,connected with one another by wired or wireless communication. Theterminal apparatuses 210 to 240 respectively include determination units212, 222, 232, 242 that determine various information such as schedulesand memory units 211, 221, 231, 241 that store various data.

FIG. 18 illustrates a sequence of an operation of the stem cellinformation management system 260. The acceptance management terminal210 stores collectable dates of the collecting institutions andexaminable dates of the examination institutions in the memory unit 221in advance (step S220), outputs the collectable dates and the examinabledates to a second medium and communicates the dates to the entrymanagement terminal 210 (step S221). The manufacturing processmanagement terminal 230 stores producible periods of the productiondevice(s) in the memory unit 231 in advance (step S222), outputs theproducible periods to a third medium (step S223), and communicates theperiods to the acceptance management terminal 220 (step S224). The stockmanagement terminal 240 stores stockable locations and stockable periodsof the stock sites in the memory unit 241 in advance (step S225),outputs the stockable locations and the stockable periods to a fifthmedium (step S226), and communicates the stockable locations andstockable periods to the manufacturing process management terminal 230(step S227).

When the entry management terminal 210 receives a manufacturing requestincluding desired collection dates together with the donor ID (stepS228), the entry management terminal 210 determines a collection date ofsomatic cells, based on whether or not one of the desired collectiondates falls upon one of the collectable dates communicated by the secondmedium (step S229). The entry management terminal 210 further determinesa transport date such that a collection kit 209 will be transportedseven days before the determined collection date (step S229). The entrymanagement terminal 210 also determines an examination date of somaticcells, based on whether or not the date obtained by adding two days fortransportation to the determined collection date falls upon one of theexaminable dates communicated by the second medium (step S229). Theentry management terminal 210 outputs the determined collection date andthe examination date to a first medium (step S230), and communicates thedates to the acceptance management terminal 220 and the manufacturingprocess management terminal 230 (step S231).

The acceptance management terminal 220 determines an acceptance date ofsomatic cells, based on whether or not the date obtained by adding sevendays for examining the somatic cells and two days for transporting thesomatic cells to the examination date communicated by the first mediumfalls within one of the producible periods communicated by the thirdmedium (step S232). In other words, the acceptance management terminal220 determines an acceptance date of somatic cells, based on thedetermined collection date and the producible periods communicated bythe third medium.

The manufacturing process management terminal 230 determines anacceptance date of somatic cells by the same procedure as the entrymanagement terminal 210 (step S233). The manufacturing processmanagement terminal 230 determines a stem cell production period so thatthe production of the stem cells may be started immediately from thedetermined acceptance date of somatic cells (step S234). In other words,the manufacturing process management terminal 230 determines a stem cellproduction period, based on the collection date of somatic cellscommunicated by the first medium and the producible periods stored inmemory. Further, the manufacturing process management terminal 230initially sets a predicted release date and time of the stem cellfreezing vial to be released from the closed production device on thedate three months after the production starting date, and determines acryopreservation period, based on whether or not the predicted releasedate and time falls within an cryopreservable period of thecryopreservation device (step S234). The manufacturing processmanagement terminal 230 then determines a shipping date of stem cells,based on whether or not the date obtained by adding four days fortransporting the stem cells to the predicted release date and time fallswithin an stockable period of the most closely located stockablelocation of the stockable locations communicated by the fifth medium(step S234). In other words, the manufacturing process managementterminal 230 determines a shipping date of stem cells, based on theproduction period of stem cells and the stock locations and stockperiods communicated by the fifth medium. The manufacturing processmanagement terminal 230 outputs the determined production period and thecryopreservation period to a fourth medium (step S235), and communicatesthese periods to the stock management terminal 240 (step S236).

The stock management terminal 240 determines a stock location and stockperiod of stem cells by the same procedure as the manufacturing processmanagement terminal 230 (step S237). In other words, the stockmanagement terminal 240 determines a stock location and stock period ofstem cells, based on the production period of stem cells communicated bythe fourth medium and the stockable locations and stockable periodsstored in memory.

The entry management terminal 210 stores the determined collection date,the transport date of transporting a collection kit, the examinationdate of somatic cells, and the like in the memory unit 211 inassociation with the donor ID, and transmits these dates to the donor(step S239). Similarly, the acceptance management terminal 220 storesthe determined acceptance date of somatic cells in the memory unit 221in association with the donor ID, and transmits the date to the donor(step S240). Similarly, the manufacturing process management terminal230 stores the determined production period, the cryopreservationperiod, and the shipping date in the memory unit 231 in association withthe donor ID, and transmits the periods and the date to the donor (stepS241). The stock management terminal 240 stores the determined stocklocation and stock period in the memory unit 241 in association with thedonor ID, and transmits the stock location and stock period to the donor(step S242).

According to the stem cell information management systems 200, 260, ineither server-based or medium-based configuration, when a manufacturingrequest is received, the determination unit of the server apparatus 201determines or the determination units of the terminal apparatuses 210 to240 determine a production schedule of stem cells according to theshortest route and the shortest time, which shortens the production timeand provides a sophisticated quality control.

In the following, modification of a schedule in response to anabnormality in the transport process, the examination process, and themanufacturing process will be described based on the stem cellinformation management system 200 with the server-based configuration.FIG. 23 to FIG. 27 illustrate a configuration and an operation of thestem cell information management system 200 in the transport process. Asillustrated in FIG. 23 , the stem cell information management system 200further includes a transport container 250 configured to contain one ormore somatic cell collection vials. The transport container 250 includesat least one of a heating and cooling device 253 connected with atemperature sensor 251 and a heating and cooling module 252, anaccumulated time measurement device 254 measuring accumulatedtransportation time of the transport container 250, a somatic cellcoagulation monitoring device 255 monitoring the coagulating state ofthe somatic cells in the somatic cell collection vial, and a vibrationmonitoring device 256 monitoring vibration of the transport container250. The transport container 250 further includes a memory 275 storingvarious data, a communication control unit in a wireless communicationwith a superordinate computer, and a CPU 258 that controls the wholetransport container 250.

As illustrated in FIG. 24 , the heating and cooling device 253 includesa temperature estimation unit 259 estimating the temperature of thesomatic cells in the transport container 250, and a heating and coolingunit 260 automatically performing heating or cooling in conjunction withthe temperature data from the temperature estimation unit so that thetemperature may be kept constant. The temperature estimation unit 259estimates the temperature of the somatic cells, based on the temperaturefrom the temperature sensor 251 and the thermal conductivity of thesomatic cell collection vial 102. The heating and cooling unit 260outputs electric current to a heating and cooling module 252 so that thetemperature data for the temperature estimation unit 259 may be equal toa target temperature (e.g., 4° C.) Further, the heating and coolingdevice 253 stores in memory an upper temperature limit and a lowertemperature limit, and issues a temperature-related abnormality alarmwhen the temperature data from the temperature estimation unit 259 isequal to or higher than the upper temperature limit or equal to or lowerthan the lower temperature limit.

The accumulated time measurement device 254 includes a timer device (notillustrated) with a start function and a stop function, and measuresaccumulated transportation time starting from the collection date andtime of the somatic cells or the release of the stem cell freezing vials103. The accumulated time measurement device 254 stores in memory a timeperiod during which the quality of the somatic cells or the stem cellscan be maintained and outputs a time-related abnormality alarm when theaccumulated transportation time exceeds the time period during which thequality can be maintained.

As illustrated in FIG. 25 , the somatic cell coagulation monitoringdevice 255 includes, an alternative current production unit 276producing alternative current, an impedance measurement unit 277measuring impedance from the alternative current applied to the somaticcells, and a somatic cell coagulation monitoring unit 278 monitoring thestate of somatic cell coagulation, based on the correlation data betweenthe impedance and the state of somatic cell coagulation stored in memoryin advance. The somatic cell coagulation monitoring device 255 stores inmemory an upper limit and a lower limit for a numerical valuerepresenting the state of coagulation (e.g., impedance, or somatic cellcoagulation value calculated from impedance), and outputs ancoagulation-related abnormality alarm when the value of somatic cellcoagulation is equal to or greater than the upper limit or equal to orsmaller than the lower limit.

The vibration monitoring device 256 is provided with a vibration sensor257 configured to detect vibration of the transport container 250(displacement in three-dimension directions, velocity, acceleration, orforce), and outputs a vibration-related abnormality alarm when anumerical value representing vibration detected by the vibration sensor257 (e.g., the integral of the absolute value of acceleration withrespect to time, as a value having a correlation with a total energy ofvibration) exceeds an upper limit.

FIG. 26 illustrates a transport table 512 containing transportinformation and FIG. 27 illustrates an operation of the stem cellinformation management system 200, based on the transport information.The transport container 250 stores in a memory 275 transport informationincluding at least one of the above-described temperature data,accumulated transportation time, a numerical value representing thestate of coagulation, a numerical value representing the vibration inassociation with at least the donor ID, and transmits the transportinformation to the server apparatus 201 serving as the superordinatecomputer 170 (step S230). When at least one of the temperature data(step S231), the accumulated transportation time (step S232), thenumerical value representing the state of coagulation (step S233), andthe numerical value representing the vibration (step S234) is out of thenormal range, the server apparatus 201 determines to output an alarm foran abnormality at the time of transport and modify the schedule (stepS235), and transmits an alarm for an abnormality at the time oftransport and the transport information to the mobile terminal 180 in aremote location (step S236).

FIG. 28 to FIG. 30 illustrate a configuration and an operation of thestem cell information management system 200 in the examination processof somatic cells. As illustrated in FIG. 28 , the stem cell informationmanagement system 200 further includes a first examination device 285configured to perform examination as to whether or not the collectedsomatic cells can be easily reprogrammed, and the first examinationdevice 285 includes at least one of a somatic cell counting device 286for counting somatic cells (e.g., the number of T cells in 1 ml ofblood, the number of NK cells, the number of B cells, and the like) anda gene expression level measurement device 287 for measuring expressionof particular genes. The first examination device 285 further includes amemory 288 storing various data, a communication control unit 289 in awireless or wired communication with the server apparatus 201 serving asthe superordinate computer, and a CPU 290 controlling the whole firstexamination device 285, stores in the memory 288 the measured somaticcell count and the presence or absence or amount of expression ofparticular genes in association with the donor ID, and transmits theinformation to the server apparatus 201 serving as the superordinatecomputer 170. According to another embodiment, the first examinationdevice 285 may include an HLA typing device, a genomic informationexamination device for examining genomic information, and the like.

As illustrated in FIG. 29 , the server apparatus 201 serving as thesuperordinate computer 170 further includes a multiple regressionanalysis unit 204 that stores in a memory unit 202 correlation databetween various data accumulated in the past and reprogramming rate andperforms multiple regression analysis based on the correlation data, anda determination unit 205 that determines a predicted reprogramming ratefor the somatic cell donor. According to another embodiment, the firstexamination device 285 may include the multiple regression analysis unit204 and a predicted reprogramming rate determination unit 205, andtransmit to the server apparatus 201 the predicted reprogramming rate,which is an indicator as to whether or not the somatic cells can beeasily reprogrammed.

According to another embodiment, the server apparatus 201 may include amachine learning unit that learns data features and patterns based onmultiple kinds of combinations of various data accumulated in the pastand reprogramming rate and a predicted reprogramming rates determinationunit that determines a predicted reprogramming rate based on the learneddata features and patterns. According to still another embodiment, theserver apparatus 201 may include a neural network production unit thatproduces a neural network based on multiple kinds of combinations ofvarious data accumulated in the past and reprogramming rates and apredicted reprogramming rate determination unit that determines apredicted reprogramming rate based on the produced neural network.Furthermore, it should be recognized that deep learning and AI may beutilized for the determination of a predicted reprogramming rate.

As illustrated in FIG. 30 , the server apparatus 201 stores examinationinformation from the first examination device (i.e., the somatic cellcount, the presence or absence or amount of particular genes. Accordingto another embodiment, HLA types, genomic information, SNPs, and thelike may be included) in the memory unit 202, in association with atleast the donor ID (step S240). The server apparatus 201 then determinesa predicted reprogramming rate based on the age, anamnesis, familymembers from whom stem cells were produced in the past, of the donor,somatic cell count, and the presence or absence and amount of particulargenes stored in memory and, when the predicted reprogramming rate is outof the normal range (e.g., less than 50%) (step S241), the serverapparatus 201 determines to output an alarm for an abnormality at thetime of examination and modify the schedule (step S242) and transmitsthe alarm for an abnormality at the time of examination and theexamination information to the mobile terminal 180 in a remote location(step S243).

FIG. 31 to FIG. 33 are flow charts illustrating operations of the stemcell information management system 200 in the manufacturing process. Thestem cell information management system 200 further includes a conveyerdevice 140 (see FIG. 1 ) that conveys at least one of a somatic cellcollection vial 102, a stem cell freezing vial 103 (empty vial), a stemcell production material vial 104, and a culture reagent vial 105 to theproduction device 101, based on the production device ID read from thevial, and a server apparatus 201 that stores in memory the stockinformation of the stem cell production material vial 104 and theculture reagent vial 105.

As illustrated in FIG. 31 , when the server apparatus 201 has determinedthat the production period of the production device 101 determined atthe time of receiving the request (step S250) is about to commence, theconveyer device 140 determines whether or not there is a somatic cellcollection vial 102 (step S251), and when there is a somatic cellcollection vial 102, the server apparatus 201 determines, based on thestock information of the stem cell production material and the culturereagent, stored in memory (step S252), to cause the conveyer device 140to convey at least one of a stem cell production material vial 104 and aculture reagent vial 105. The conveyer device 140 conveys a somatic cellcollection vial 102, a stem cell freezing vial 103 (empty vial), a stemcell production material vial 104, and a culture reagent vial 105 to theproduction device 101, based on the production device ID (step S253).When there is no somatic cell collection vial 102, or there is noinventory of at least one of stem cell freezing vials 103 (empty vial),stem cell production material vials 104, and culture reagent vials 105,the server apparatus 201 determines to output an alarm for anabnormality at the time of production and modify the schedule (stepS254) and transmits the alarm for an abnormality at the time ofproduction to the mobile terminal (step S255).

As illustrated in FIG. 32 , the stem cell information management system200 further includes a vision sensor for acquiring data in theproduction device 101 (e.g., the vision sensor 137 of the drive device130 illustrated in FIG. 6 ), and the server apparatus 201 stores datafrom the vision sensor 137 in the memory unit 202 (step S260). Theserver apparatus 201 determines, based on the data from the visionsensor 137 stored in the memory, whether or not the size or growth speedof the stem cell clusters is within the normal range (step S261),whether or not the stem cell count is within the normal range (stepS262), whether or not the shape of the stem cells is within the normalrange (step S263), whether or not the color tone or pH of the culturereagent is within the normal range (step S264), and whether or notdifferentiated cells having differentiated from the stem cells arepresent (step S265). When any one of these pieces of productioninformation is out of the normal range, the server apparatus 201determines to output an alarm for an abnormality at the time ofproduction and modify the schedule (including modifying the predictedrelease date and time) (step S266), and transmits the alarm for anabnormality at the time of production and the production information tothe mobile terminal 180 in a remote location (step S267).

As illustrated in FIG. 33 , when the server apparatus 201 has determinedthat it is ten minutes before the predicted release date and time of thestem cell freezing vial 102 determined at the time of receiving therequest (step S270), the server apparatus 201 causes the conveyer device142 to start detecting a release of a stem cell freezing vial 103 withthe vision sensor 145 (step S271). When the conveyer device 142 detectsa release of a stem cell freezing vial 103 (step S272), the conveyerdevice 142 conveys the stem cell freezing vial 103 to thecryopreservation device 120 (step S273). When the conveyer device 142does not detect a release of a stem cell freezing vial 103 at thepredicted release date and time (step S274), the conveyer device 142repeats the detection until ten minutes elapse from the predictedrelease date and time, and when ten minutes have elapsed, the serverapparatus 201 outputs an alarm for an abnormality at the time ofproduction and modifies the schedule (step S275) and transmits the alarmfor an abnormality at the time of production and the productioninformation to the mobile terminal 180 in a remote location (step S276).

FIG. 34 to FIG. 37 illustrate a configuration and an operation of thestem cell information management system 200 in the examination processof stem cells. As illustrated in FIG. 34 , the stem cell informationmanagement system 200 further includes at least one of a secondexamination device 291 that includes a genomic information examinationdevice 279 for somatic cells and stem cells, and a third examinationdevice 295 that includes an HLA typing device 280 examining HLA types ofsomatic cells and stem cells. The second examination device 291 or thethird examination device 295 further includes a memory 292, 296 storingvarious data, a communication control unit 293, 297 in a wireless orwired communication with the server apparatus 201 serving as thesuperordinate computer, and a CPU 294, 298 controlling the whole secondexamination device 291 or the whole third examination device 295, andstores in a memory 292, 296 the genomic information measured of thesomatic cells and the stem cells or the HLA types measured of thesomatic cells and the stem cells in association with the donor ID readfrom the vial, and transmits the genomic information or the HLA types tothe server apparatus 201 serving as the superordinate computer 170.According to another embodiment, the stem cell information managementsystem 200 may include both of the second examination device 291 and thethird examination device 295. According to still another embodiment, thestem cell information management system 200 may include a fourthexamination device that examines SNPs or genome sequences of somaticcells and stem cells.

As illustrated in FIG. 35 and FIG. 36 , the server apparatus 201 servingas the superordinate computer 170 further includes an identitydetermination unit 206 that determines whether or not the genomicinformation of the somatic cells is identical to that of the stem cells,or whether or not the HLA types of the somatic cells are identical tothose of the stem cells. According to another embodiment, the secondexamination device 291 or the third examination device 295, not theserver apparatus 201, may include the identity determination unit 206.According to still another embodiment, the server apparatus 201 mayinclude an identity determination unit that determines whether or notthe SNPs or genome sequences are identical.

As illustrated in FIG. 37 , the server apparatus 201 stores theexamination information from the second examination device 291 or thethird examination device 295 (i.e., genomic information or HLA types ofthe somatic cells and the stem cells) in the memory unit 202 inassociation with the donor ID read from the vial (step S280). When thegenomic information or the HLA types are not identical between thesomatic cells and the stem cells (step S281), the server apparatus 201determines to output an alarm for an abnormality at the time ofexamination and to modify the schedule (step S282), and transmits thealarm for an abnormality at the time of examination and the examinationinformation to the mobile terminal 180 in a remote location (step S283).

FIG. 38 is a block diagram of an application of the FIELD system to thestem cell information management system 200 according to the presentembodiment. The stem cell manufacturing system 200 further includes acontrol device 284 including interface software 282 and work software283, and input devices connected by wired or wireless communication withthe control device 284 and inputting information in respectiveprocesses. The input devices may be, for example, the transportcontainer 250, the first examination device 285, and the drive device130. According to another embodiment, the input devices may be, forexample, input devices configured to input information in respectiveprocesses manually.

The control device 284, for example, receives a first electric currentvalue of the forward scattered light and a second electric current valueof the back-scattered light and the like of the first to the third cellsorters from moment to moment from the first examination device 285,receives temperature data from the temperature estimation unit,impedance from the somatic cell coagulation monitoring device, data fromthe vision sensor, and the like from moment to moment from one or moretransport containers 250, and receives electric current values of thefirst to the fourth pumps, voltage values of the first to the thirdswitches, data from the vision sensor, and the like from moment tomoment from one or more drive devices 130. Since a large number of inputdevices of many kinds send out pieces of information unique to a largenumber of components of many kinds, it is not possible to recognize, forexample, which cell sorter of which examination device is measuring cellcount, cell sizes, cell strain, and the like. To address this, theinterface software converts the information formatted in data formatsunique to the input devices into information formatted in a data formatunique to the work software. The data format unique to the work softwareis formed with data models having a data structure of tree type ornetwork type indicating subordination relationship of the components ofeach input device, and the various data models are stored in a memory ofthe control device 284 in advance. To facilitate understanding, forexample, a first electric current value and a second electric currentvalue of the examination device 285, a piece of information unique tothe input device, is converted to “examination device ID/third cellsorter/first electric current value/cell count/cell size”, which is in astructured data format unique to the work software. This conversiongives the work software an instant access to data of a large number ofcomponents of many kinds in a large number of input devices of manykinds.

According to the above-described stem cell information management system200, taking into consideration the production schedules of a pluralityof closed production devices 101 at the time of receiving amanufacturing request, a schedule is determined according to theshortest route and the shortest time, which shortens the production timeand provides a sophisticated quality control. At the time of receiving arequest, the somatic cell collection vial 102 and the stem cell freezingvial 103 of the closed container are equipped with an individualidentification device 106 containing the donor ID as well as at leastone of the entry ID, the transport ID, the acceptance ID, themanufacturer ID, the production device ID, the cryopreservation deviceID, and the stock site ID, which prevents cross contamination andensures traceability in case of an abnormality. Furthermore, applyingthe FIELD system allows determination to output an abnormality alarm andmodify the schedule at the time of transport, examination,manufacturing, and stock, based on big data from a large number ofcomponents of many kinds in a large number of input devices of manykinds, which shortens the production time, provides a sophisticatedquality control, and solves human resource shortages.

3. Cell Transport Apparatus

FIG. 39 and FIG. 40 are perspective views of a somatic cell transportcontainer 301 and a stem cell transport container 302 for the celltransport apparatus 300 according to the present embodiment. Asillustrated in FIG. 39 , the somatic cell transport container 301 isconfigured to contain one or more somatic cell collection vials 102equipped with an individual identification device 106, which at leastcontain a donor ID, a production device ID, and the like. As illustratedin in FIG. 40 , the stem cell transport container 302 is configured tocontain one or more stem cell freezing vials 103 equipped with anindividual identification device 106, which at least contains a donorID, a production device ID, a stock site ID, and the like. According toanother embodiment, the stem cell transport container 302 may be acryopreservation device 120 illustrated in FIG. 5 . Although a system inwhich iPS cells are produced from blood cells will be describedaccording to the present embodiment, it should be understood that theinvention can be applied to a system in which iPS cells are producedfrom skin-derived cells, a system in which ES cells are produced fromembryonic cells, and other systems.

As illustrated in FIG. 2 and FIG. 14 , the cell transport apparatus 300further includes a reader device 107 configured to read the donor ID,the production device ID, the stock site ID, and the like contained inthe individual identification device 106, and a transport means fortransporting the somatic cell transport container 301 to the closedproduction device 101, based on the read production device ID, ortransporting the stem cell transport container 302 to the stem cellstock site, based on the read stock site ID, and the transport meansincludes at least one of automobile, railway, aircraft, ship, and robot.According to this configuration of the cell transport apparatus 300,cross contamination is prevented even when stem cells are manufacturedconcurrently in one or more closed production device 101.

As illustrated in FIG. 23 and FIG. 24 , the somatic cell transportcontainer 301 further includes a heat retaining means for keeping thetemperature inside the transport container constant, and the heatretaining means is a heating and cooling device 253 that includes atemperature estimation unit 259 estimating the temperature of thesomatic cells in the transport container, and a heating and cooling unit260 automatically performing heating or cooling in conjunction with thetemperature data outputted by the temperature estimation unit 259 sothat the temperature may be kept constant. The heating and coolingdevice 253 stores in memory an upper temperature limit and a lowertemperature limit and, when the temperature data from the temperatureestimation unit 259 is equal to or higher than the upper temperaturelimit or equal to or lower than the lower temperature limit, outputs atemperature-related abnormality alarm. According to another embodiment,the stem cell transport container 302 may include such a heating andcooling configuration.

FIG. 41 is a block diagram of the stem cell transport container 302according to the present embodiment. As illustrated in FIG. 40 and FIG.41 , the stem cell transport container 302 includes a heat retainingmeans for keeping the temperature inside the transport containerconstant, and the heat retaining means includes a refrigerant 303 forcooling or freezing the stem cells in the transport container, arefrigerant remaining amount sensor 129 configured to detect theremaining amount of the refrigerant, a reserve tank 305 detachablyconnected with the transport container and containing reserverefrigerant, and a reserve refrigerant supply device 306 supplyingreserve refrigerant, based on the remaining amount of the refrigerant.The stem cell transport container 302 further includes a memory 307storing various data, a CPU 308 controlling the whole stem celltransport container, and a communication control unit 309 in a wirelesscommunication with a superordinate computer. According to anotherembodiment, the somatic cell transport container 301 may include such aconfiguration for supplying reserve refrigerant.

As illustrated in FIG. 41 , the stem cell transport container 302further includes a reserve refrigerant remaining amount sensor 310configured to detect the remaining amount of the reserve refrigerant,and a memory 307 configured to store an upper remaining amount limit anda lower remaining amount limit of the reserve refrigerant and, when theremaining amount of the reserve refrigerant is equal to or more than theupper remaining amount limit or equal to or less than the lowerremaining amount limit, outputs a remaining-amount-related abnormalityalarm. According to another embodiment, the somatic cell transportcontainer 301 may outputs the remaining-amount-related abnormalityalarm.

As illustrated in FIG. 24 , the somatic cell transport container 301 andthe stem cell transport container 302 may include an accumulated timemeasurement device 254 measuring accumulated transportation time, andthe accumulated time measurement device 254 starts to measure theaccumulated transportation time from the collection date and time of thesomatic cells or the release date and time of the stem cell freezingvial from the closed production device. The accumulated time measurementdevice 254 stores in memory a time period during which the quality ofthe somatic cells or the stem cells can be maintained and outputs atime-related abnormality alarm when the accumulated transportation timeexceeds the time period during which the quality can be maintained.

FIG. 42 is a flow chart illustrating an operation of a cell transportapparatus 300 according to the present embodiment. When at least one ofthe data from the temperature estimation unit (step S300), the remainingamount of the reserve refrigerant (step S301), the accumulatedtransportation time (step S302), and the vibration value (step S303) isout of the normal range or within the abnormal range, the transportcontainers 301, 302 output a corresponding alarm among thetemperature-related abnormality alarm (step S304), theremaining-amount-related abnormality alarm (step S305) the time-relatedabnormality alarm (step S306) and the vibration-related abnormalityalarm (step S307), and transmit the alarm to the mobile terminal 180 ina remote location by wireless communication.

FIG. 43 is a functional block diagram of an application of the FIELDsystem to the cell transport apparatus 300 according to the presentembodiment. The cell transport apparatus 300 further includes a controldevice 320 including interface software 321 and work software 322, andinput devices connected by wired or wireless communication with thecontrol device 322 and inputting information in the transport process.The input devices may be, for example, the above-described somatic celltransport container 301 and the stem cell transport container 302.According to another embodiment, the input devices may be input devicesinputting information in the transport process.

The control device 320, for example, receives resistance values of thetemperature sensor, temperature data from the temperature estimationunit, impedance of the somatic cell coagulation monitoring device,voltage values of the refrigerant remaining amount sensor, voltagevalues of the reserve refrigerant remaining amount sensor, data from thevision sensor, and the like from moment to moment from one or moretransport containers 301, 302. Since a large number of input devicessend out pieces of information unique to a large number of components ofmany kinds, it is not possible to easily recognize, for example, whichvial of which transport container an impedance relates to. To addressthis, the interface software converts the information formatted in dataformats unique to the input devices into information formatted in a dataformat unique to the work software. The data format unique to the worksoftware is formed with data models having a data structure of tree typeor network type indicating subordination relationship of the componentsof each input device, and the various data models are stored in a memoryof the control device 320 in advance. To facilitate understanding, forexample, an impedance of the somatic cell coagulation monitoring deviceof a transport container, a piece of information unique to the inputdevice, is converted to “transport container ID/somatic cell coagulationmonitoring device/fourth somatic cell collection vial/impedance/somaticcell coagulation value”, which is in a structured data format unique tothe work software. This conversion gives the work software an instantaccess to data of a large number of components of many kinds in a largenumber of input devices.

According to the above-described cell transport apparatus 300, since thesomatic cell collection vial 102 contains the donor ID and theproduction device ID, or the stem cell freezing vial 103 contains thedonor ID, the production device ID, and the stock site ID, crosscontamination is prevented and traceability in case of abnormality isensured. Furthermore, applying the FIELD system allows an abnormalityalarm to be outputted and transmitted instantly, based on informationunique to a large number of components of many kinds in a large numberof input devices, which provides a sophisticated quality control,shortens the production time, and solves human resource shortages.

4. Stem Cell Frozen Storage Apparatus

FIG. 44 and FIG. 45 illustrate a configuration of the stem cell frozenstorage apparatus 400 according to the present embodiment. Asillustrated in FIG. 44 , the stem cell frozen storage apparatus 400includes one or more cryopreservation devices 120 configured tocryopreserve stem cell freezing vials 102, a storehouse 401 storing thecryopreservation devices 120, a conveyer device 402 configured to conveythe cryopreservation devices 120 into and out of the storehouse 401, arefrigerant storage tank 404 connected with the one or morecryopreservation devices 120 via a refrigerant supply line 403. Theconveyer device 402 is configured with a robot autonomously performingwork according to a teaching program, and connects the one or morecryopreservation devices 120 with the refrigerant supply line 403.

As described with reference to FIG. 5 , each cryopreservation device 120includes a container unit 124 configured to contain one or more stemcell freezing vials 103 and a refrigerant chamber 125 configured tocontain a refrigerant for freezing the stem cell freezing vial(s) 103, arefrigerant remaining amount sensor 129 configured to detect theremaining amount of the refrigerant, a temperature sensor 128 configuredto measure temperature in the container unit 124, and a vision sensor127 configured to detect presence of stem cells in the stem cellfreezing vial(s) 103 (or presence of frozen liquid). The individualidentification device 106 of each stem cell freezing vial 103 in thecryopreservation device 120 includes the donor ID as well as donorinformation including at least one of informed consent, nationality,address, sex, age, blood type, anamnesis, prescription history, healthcheck results, and family members from whom stem cells are produced inthe past, of the somatic cell donor. This makes it possible to easilyidentify the individual to whom the stem cell freezing vial 103 belongsto as well as the characteristics of the individual even in the stemcell stock site stocking many cryopreservation devices 120.

As illustrated in FIG. 5 , the cryopreservation device 120 furtherincludes a presence sensor 121 detecting presence or absence of a stemcell freezing vial 103. The stem cell frozen storage apparatus 400further includes a conveyer device (not illustrated) configured toconvey a stem cell freezing vial 103 into and out of the container unit124 of the cryopreservation device 120, and the conveyer device (notillustrated) conveys a stem cell freezing vial 103 when there is no stemcell freezing vial 103 in the container unit 124 of the cryopreservationdevice 120, based on the detected presence or absence of a stem cellfreezing vial 103. The conveyer device (not illustrated) is configuredwith a robot autonomously performing work according to a teachingprogram.

As illustrated in FIG. 44 and FIG. 45 , the stem cell frozen storageapparatus 400 further includes a control device 406 monitoring andcontrolling operational status of one or more cryopreservation devices120, based on information from at least one of the remaining amountsensor of the cryopreservation device(s) 120, the temperature sensor,and the vision sensor, and the control device 406 stores the operationalstatus of the cryopreservation device(s) 120 in the memory 407 inassociation with time information and the donor ID and the like asrecord information. Further, the control device 406 stores in the memory407 at least one of a normal range and an abnormal range of theoperational status and, when the operational status is at least one ofbeing out of the normal range and being within the abnormal range,outputs an abnormality alarm at least in association with the donor IDand transmits an abnormal alarm to a superordinate computer 170 or amobile terminal 180 in a remote location by wired or wirelesscommunication.

FIG. 46 is a functional block diagram of an application of the FIELDsystem to the stem cell frozen storage apparatus 400. The control device406 includes interface software 410, work software 411, and inputdevices connected by wired or wireless communication with the controldevice 406 and inputting information in the stock process. The inputdevices may be, for example, many cryopreservation devices 120.According to another embodiment, the input devices may be input devicesconfigured to input information in the stock process.

The control device 406, for example, receives resistance values of thetemperature sensor, voltage values of the remaining amount sensor, dataform the vision sensor, voltage values of the supply valve 412, and thelike from moment to moment from one or more cryopreservation devices120. Since a large number of input devices send out pieces ofinformation unique to a large number of components of many of kinds, itis not possible to easily recognize, for example, to which component ofwhich cryopreservation device 120 a certain voltage relates and what itindicates. To address this, the interface software converts theinformation formatted in data formats unique to the input devices intoinformation formatted in a data format unique to the work software. Thedata format unique to the work software is formed with data modelshaving a data structure of tree type or network type indicatingsubordination relationship of the components of each input device, andthe various data models are stored in a memory of the control device 407in advance. To facilitate understanding, for example, data from thevision sensor of a cryopreservation device 120, a piece of informationunique to the input device, is converted to “cryopreservation deviceID/vision sensor/data/presence or absence of stem cells (presence orabsence of frozen liquid)”, which is in a structured data format uniqueto the work software. This conversion gives the work software an instantaccess to data of a large number of components of many kinds in a largenumber of input devices.

The above-described stem cell frozen storage apparatus 400 allows themonitoring of the operational status of the cryopreservation device(s)120 and management of the presence or absence of stem cells (or presenceor absence of frozen liquid) in the cryopreservation device(s) 120 in astem cell stock site with a long-term stock function. Furthermore,applying the FIELD system allows an abnormality alarm to be outputtedand transmitted instantly, based on information from a large number ofcomponents of many kinds of many cryopreservation devices 120, whichprovides a sophisticated quality control, shortens the production time,and solves human resource shortages.

The software in the above-described embodiments may be provided byrecording it in a machine-readable non-volatile recording medium,CD-ROM, or the like. Although various embodiments have been describedherein, the present invention is not limited to the above-describedembodiments, and it should be understood that various modifications canbe made within the scope described in the appended claims.

The invention claimed is:
 1. A stem cell frozen storage apparatus forcryopreserving stem cells produced from somatic cells collected from asomatic cell donor, the apparatus comprising: a stem cell freezingvial(s) released from one or more closed production device(s) andcontaining frozen stem cells; one or more cryopreservation device(s)configured to cryopreserve the stem cell freezing vial(s); a storehousethat stores the cryopreservation device(s); and a first conveyer deviceconfigured to convey the cryopreservation device(s) into and out of thestorehouse, each of the cryopreservation device(s) comprising: acontainer unit configured to receive one or more of the stem cellfreezing vial(s), a presence sensor configured to detect presence of astem cell freezing vial received in the container unit, a vision sensorother than the presence sensor and configured to detect presence offrozen liquid in the stem cell freezing vial received in the containerunit, and a refrigerant chamber configured to contain a refrigerant forfreezing the stem cell freezing vial(s).
 2. The stem cell frozen storageapparatus according to claim 1, the cryopreservation device(s)comprising at least one of: a remaining amount sensor configured todetect a remaining amount of the refrigerant; or a temperature sensorconfigured to measure temperature of the container unit.
 3. The stemcell frozen storage apparatus according to claim 2, further comprising acontrol device configured to monitor and control operational status ofthe cryopreservation device(s), based on information from the at leastone of the remaining amount sensor or the temperature sensor, and thevision sensor.
 4. The stem cell frozen storage apparatus according toclaim 3, wherein the control device comprises a memory device configuredto store as record information the operational status of thecryopreservation device(s) in association with time information.
 5. Thestem cell frozen storage apparatus according to claim 4, wherein thestem cell freezing vial(s) is/are equipped with an individualidentification device containing donor identification information foridentifying the somatic cell donor, and wherein the memory device storesat least the donor identification information in association with therecord information.
 6. The stem cell frozen storage apparatus accordingto claim 5, wherein the individual identification device contains donorinformation including at least one of informed consent, nationality,address, sex, age, blood type, anamnesis, prescription history, healthcheck results, and family members from whom stem cells are produced inthe past, of the somatic cell donor.
 7. The stem cell frozen storageapparatus according to claim 5, wherein the memory device stores atleast one of a normal range and an abnormal range of the operationalstatus as first information, and the control device is configured tooutput an abnormality alarm at least in association with the donoridentification information when the operational status is at least oneof being out of the normal range and being within the abnormal range ofthe first information.
 8. The stem cell frozen storage apparatusaccording to claim 7, wherein at least one of the record information andthe abnormality alarm is transmitted to a mobile terminal in a remotelocation by wireless communication.
 9. The stem cell frozen storageapparatus according to claim 3, the control device comprising: interfacesoftware and work software; and an input device in wired or wirelesscommunication with the control device and configured to inputinformation in a stock process; wherein the interface software isconfigured to convert information formatted in a data format unique tothe input device into information formatted in a data format unique tothe work software.
 10. The stem cell frozen storage apparatus accordingto claim 3, wherein the cryopreservation device(s) comprises all of theremaining amount sensor, the temperature sensor, and the vision sensor,and wherein the control device is configured to monitor and control theoperational status of the cryopreservation device(s), based oninformation of all of the remaining amount sensor, the temperaturesensor, and the vision sensor.
 11. The stem cell frozen storageapparatus according to claim 3, wherein the cryopreservation device(s)comprises a supply valve for supplying the refrigerant to therefrigerant chamber, wherein the stem cell frozen storage apparatusfurther comprises a refrigerant supply line that connects to the supplyvalve and a refrigerant storage tank that connects with thecryopreservation device(s) via the refrigerant supply line, and whereinthe control device is configured to control the supply valve on therefrigerant supply line, based on information of all of the remainingamount sensor, the temperature sensor, and the vision sensor.
 12. Thestem cell frozen storage apparatus according to claim 2, furthercomprising a second conveyer device configured to convey a stem cellfreezing vial(s) into and out of the container unit of thecryopreservation device(s).
 13. The stem cell frozen storage apparatusaccording to claim 12, wherein the second conveyer device is configuredto convey a stem cell freezing vial(s) in response to the presencesensor detecting no stem cell freezing vial in the container unit of thecryopreservation device(s).
 14. The stem cell frozen storage apparatusaccording to claim 13, wherein the first conveyer device or the secondconveyer device is a robot.
 15. The stem cell frozen storage apparatusaccording to claim 1, wherein the cryopreservation device(s) comprises asupply valve for supplying the refrigerant to the refrigerant chamber,and wherein the stem cell frozen storage apparatus further comprises arefrigerant supply line that connects to the supply valve and arefrigerant storage tank that connects with the cryopreservationdevice(s) via the refrigerant supply line.
 16. The stem cell frozenstorage apparatus according to claim 1, wherein the cryopreservationdevice(s) comprises a supply valve for supplying the refrigerant to therefrigerant chamber, wherein the stem cell frozen storage apparatusfurther comprises a refrigerant supply line that connects to the supplyvalve and a refrigerant storage tank that connects with thecryopreservation device(s) via the refrigerant supply line, and whereinthe first conveyer device is configured to connect the cryopreservationdevice(s) with the refrigerant supply line.
 17. The stem cell frozenstorage apparatus according to claim 1, wherein the refrigerant chamberof the cryopreservation device(s) is vacuum insulated.
 18. The stem cellfrozen storage apparatus according to claim 1, wherein each of thecryopreservation device(s) comprises a plurality of slots eachconfigured to receive one stem cell freezing vial, and a plurality ofpresence sensors corresponding to the plurality of slots, each of theplurality of presence sensors configured to detect presence or absenceof a stem cell freezing vial in the corresponding slot among theplurality of slots.